POS1444 FLT1 AND EPHB2 ARE NOVEL GENETIC MARKERS ASSOCIATED WITH PANCREATITIS IN PATIENTS TAKING AZATHIOPRINE FOR IMMUNE-MEDIATED CONDITIONS: INTEGRATING GENOME- AND TRANSCRIPTOME-WIDE ASSOCIATION STUDIES
Authors: S. Shah, T. Reese, J. Zanussi, A. Dickson, L. Daniel, R. Tao, T. Miller-Fleming, P. Straub, A. Hung, P. Nepal, W. Q. Wei, E. Phillips, N. Cox, C. M. Stein, Q. Feng, C. P. Chung
Journal: Annals of the Rheumatic Diseases (2022)

Background Azathioprine (AZA) is a thiopurine immunosuppressant medication used to treat a variety of immune-mediated diseases. Unfortunately, its use is limited by adverse effects. Pancreatitis, a potentially severe, life-threatening side effect is independent of dose and necessitates AZA discontinuation given the high risk of recurrent pancreatitis with continued use or re-challenge. The mechanisms driving pancreatitis are unclear. While classic thiopurine-induced acute pancreatitis (TIAP) has been associated with HLA haplotypes, most patients taking AZA and presenting with pancreatitis do not fulfill the stringent criteria for TIAP. Objectives To identify genetic risk factors for pancreatitis in patients taking azathioprine for immune-mediated conditions. Methods Using a biobank linked to electronic health records (EHR) from a tertiary center, we identified new users of AZA. Patients were excluded if the primary indication for AZA was organ transplant or if there was a history of pancreatitis prior to AZA use. The analysis was restricted to patients with EHR-reported race as White due to insufficient case counts for the non-White group. We then identified patients with amylase or lipase values that exceeded twice the upper limit of normal (“&gt;2x ULN”) or with ICD-9/ICD-10 codes for acute pancreatitis. Each record was manually reviewed to confirm the timing of AZA use in relation to laboratory derangements or ICD coding, as well as to further classify patients into three increasingly strict, but not exclusive categories: 1) pancreatic injury (amylase or lipase &gt;2x ULN); 2) acute pancreatitis 1 , or 3) TIAP 2 . We completed genotyping with Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content data, employed Michigan Imputation servers for genetic imputation, and used PrediXcan (GTEx v8) to impute gene expression. We then conducted genome-wide association and transcriptome-wide association studies (GWAS, TWAS). Acknowledging the relatively small overall cohort, and possible imbalance of cases vs controls, we used the Firth logistic regression method, which is a penalized likelihood-based method. Results We studied 2127 AZA users (35.4% male; mean 44.5+/-17.2 years). The median AZA dose was 100mg/day (IQR: 50-125mg/day). Rheumatologic conditions (56.9%) and inflammatory bowel disease (40.4%) comprised the most common primary indications for AZA. Pancreatic injury, pancreatitis, and TIAP were diagnosed in 42 (2.0%), 16 (0.8%), and 9 (0.4%) patients, respectively. GWAS identified several significantly associated genes, many with overlapping TWAS findings in the pancreas and liver (Figure 1). From these, the two protein-encoding genes Fms Related Receptor Tyrosine Kinase-1 ( FLT1 ) and Ephrin type-B receptor-2 ( EPHB2 ) overlapped in two or more pancreatitis phenotypes in the TWAS and GWAS, respectively. EPHB2 was associated with a 8.6-fold (P=1.84 x 10 -8 ) and a 31.4-fold (P=2.87x 10 -8 ) higher likelihood of pancreatic injury and TIAP, respectively. Figure 1. Conclusion FLT1— a gene that encodes a receptor tyrosine kinase and is a member of the vascular endothelial growth factor receptor (VEGFR) family—and EPHB2 —a gene that encodes a member of the Eph receptor family, which is the largest subgroup of the receptor tyrosine kinase family—are novel genetic markers associated with pancreatitis in patients taking AZA. VEGF can potentiate inflammation and the pancreas microenvironment is known to promote VEGF expression, which has been linked to pancreatic cancer development; anti-VEGF treatments have been investigated both for mitigating inflammation and also anti-pancreatic cancer treatment. Future studies validating our findings in AZA-induced pancreatitis are warranted. References [1]Crockett et al. Gastroenterology (2018). 154 (4):1096-1101. [2]Heap et al. Nature Genetics (2014). 46 :1131-1134 Disclosure of Interests Shailja Shah Consultant of: ad hoc consultant for Phathom pharmaceuticals, Tyler Reese: None declared, Jacy Zanussi: None declared, Alyson Dickson: None declared, Laura Daniel: None declared, Ran Tao: None declared, Tyne Miller-Fleming: None declared, Peter Straub: None declared, Adriana Hung: None declared, Puran Nepal: None declared, Wei-Qi Wei: None declared, Elizabeth Phillips: None declared, Nancy Cox: None declared, Charles M. Stein: None declared, QiPeng Feng: None declared, Cecilia P. Chung: None declared